UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460
OFFICE OF CHEM I CAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM Date: September 16, 20 14 SUBJECT : Metolachlor: Tier I Review of Human Incidents

PC Code: 10880 1,108800 Decision No.: 49150 I Petition No. : NA Ris k Assess ment T ype: NA TXRNo.: NA MRIDNo.:NA OP Barcode: 042080 1 Registration No

. : NA Regulato ry Action: NA Case No.: NA CAS No. : 51218

-45-2, 87392-12-9 40 CFR: NA Ver.Apr.08 F ROM: E lizabeth Evans, Environmental Protection Specialist

# ~~_Q Shanna Recore, Industrial Hygienist**~ ~**  j/)f' Caro l Christensen, Ph.D.,

### Epidemiologist.£1~VJ 

## L Toxicology and Epidemiology Branch ( Healt h Effects Division (7509 P)

# 1/,11~**!IJ~ -iliV**  THROUGH: David Mi ll er, Acting Branch Chie{A. _/LJ' /V

### t1. Toxicology and Epidemio logy Branch Health Effects Division (7509P) TO: Jessica Kidwell, Risk Assessor Risk Assessment Branch 

### I V Health Effects Division (7509P) and Kaitlin Keller, Chemical Review Manager Risk Management & Implementation Branch 3 Pesticide Re-evaluation Division (7508P) Summary and Conclusions There does not appear to be a concern at this time that would warrant further investigation, since there is a low frequency of incidents involving meto lachl or reported to ID S and SENSORPesticides. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the ri sk assessment. AHS study results indicate
Page 

### 1 of7a possible association with lung cancer (observed in two studies within the cohort); however, chance and bias (exposure classification, exposure algorithm, and control for the effect of smoking) cannot be ruled out. EPA will continue to monitor this literature. Detailed Review I. 

### ACTION REQUESTED This review is intended to fulfill our requirement to docket summaries of incident data that were reported to the Agency, as well as to ensure human incident data and the Agricultural Health Study (AHS) are part ofthe problem formulation phase ofregistration review. Reports of adverse health effects allegedly due to a specific pesticide exposure 

### (i.e., an ''incident") are largely self-reported and therefore, generally speaking, neither exposure to a pesticide or reported symptom (or the connection between the two) is validated or otherwise confirmed. Typically, causation cannot be determined based on incident data. However, incident information can be an important source offeedback to the Agency: incidents of severe outcome , or a suggested pattern or trend among less severe incidents , can signal the Agency to f urther investigate a particular chemical or product. Observational epidemiology studies relate the risk of disease, 

### -e.g., cancer, and exposure to an agent such as a pesticide product in the general population or specific sub-groups like pesticide applicators. 

### II . BACKGROUND Metolachlor is a broad spectrum herbicide used for general weed control in many agricultural food and feed crops (primarily corn, soybeans and sorghum), and on lawns and turf , ornamental plants, trees, shrubs and vines, rights of way, fencerows and hedgerows, and in forestry. The emulsifiable concentrate formulation is most commonly used, but granular formulations also are available. Ground application is the use method of choice for all sites, although aerial , irrigation, and chemigation application methods also are permitted. For this evaluation, both the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk-Pesticides (S ENSOR) databases were consulted for pesticide incident data on the active ingredient metolachlor (pc codes: 108801 , 1

08800). The purpose of the database search is to identify potential patterns in the frequency and severity of the health effects attributed to metolachlor exposure. Metolachlor is included in the AHS, and therefore a brief summary of these results are included herein. 

### III. RESULTS/DISCUSSION

a. IDS (Incident Data System) OPP's IDS includes reports of alleged human health incidents f rom various sources, including mandatory'Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports from registrants, other federal and state health and environmental agencies, and individual consumers. Since 1992, OPP has compiled these reports in IDS. IDS contains reports from across the U.S. and most incidents have all relevant product information recorded. Reports Page 2 of7submitted to the IDS represent anecdotal reports or allegations only, unless ot herwise stated in the report. IDS records incidents in one of two modules: Main IDS and Aggregate IDS:

o Main IDS contains incidents resulting in higher severity outcomes and provides more detail with regard to case specifics. This system stores incident data for death, major and moderate incidents, and it includes information about the location, date and nature of the incident. Main IDS incidents involving only one active ingredient (as opposed to pesticide products with multiple active ingredients) are considered to provide more certain information about the potential effects of exposure from the pesticide.

o Aggregate IDS contains incidents resulting in less severe human incidents (minor, unknown, or no effects outcomes). These are reported by registrants only as counts in what are aggregate summaries. For the Main IDS, from January 1, 2006 to May 28,2014, there were 0 incidents reported invo l ving metolachlor in the database. In Aggregate IDS, from January 1, 2009 to May 28, 2014, there were 0 incident reported involving metolachlor in the database. This incident was classified as minor severity.



### b. SENSOR-Pesticides The SENSOR-Pesticides database covers 11 states from 1998

-2010, although reporting varies from state to state. Cases ofpesticide-related illnesses are ascertained from a variety of sources, including: reports from local Poison Control Centers, state Department ofLabor workers' compensation claims when reported by physicians, reports from State Departments of Agriculture, and physician reports to state Departments of Health. Although both occupational and non-occupational incidents are included in the database, SENSOR-Pesticides focuses on occupational pesticide incidents, and is ofparticular value in providing that information. The state coordinator at each of the 11 respective state Departments of Health conducts case followup activities such as obtaining medical records to verify symptoms and severity. Using standardized protocol and case definitions derived from poison center reporting, the state SENSOR-Pesticide coordinator enters the incident information into the state-based system which is sent to NIOSH annually to be aggregated. A query of SENOSR

-Pesticides 1998

-20 10 identifies a total of 19 cases, stemming from 16 events, involving metolachlor (pc codes 108801 and 108800). Five ofthese cases involves a single active ingredient which will be analyzed for this memo. Two cases were moderate in severity and three cases were low in severity. The two moderate severity cases occurred in California is 1998 and 2002 respectively, however the case narratives were not provided for these two cases. For the remaining three low severity cases, one involved a splash during mixing and loading of the product, one case had a rash on his face after working in a treated field, and

Page 3 of7one case involved drift onto a residential bystander from a field lf4 to Y2 miles away in windy conditions.

Tab l e2

. SENSOR-Pesticides 199 8

-201 0 Health Eff e cts Reported f or MetolachJor Cases

Health Effect Frequency Dermal 1 Ocula r 2 Nervous System 0 Gastrointestinal I Respiratory 2 Misce llaneous I Cardiovascular' I Renal 0 

### * Cases may report multiple health effects

c. Agricultural Health Study (AHS) The AHS is a high quality, prospective epidemiology study evalua ting the pot ential association between pesticide use and various human health outcomes including both cancer and non-cancer (e.g., respiratory health) health effects. The AHS includes approximately 90,000 private and commercial pesticide applicators and their spouses. If there are AHS findings relevant to a particular pesticide going through registration review, the Agency will ensure they are considered in the problem formulation/scoping phase of the process and, if appropriate, fully reviewed in the risk assessment phase of the process. Metolachlor is a widely used herbicide; in the Agricultural Health Study (AHS) 47% ofparticipants report ever-using the pesticides in their lifetime (at least one time use). US EPA classifies metolachlor (and S-metolachlor) as a Group C "possible" human carcinogen. In an analysis of metolachlor use and various anatomical cancer sites (a cohort analysis), authors reported no overall increased risk of all cancers combined (relative risk (RR) T3upper v. T1: 1.01 (95% confidence interval ((95% CI) 0.87 , 1.30), p trend 0.98) among 50, 193 private and commercial pesticide applicators, nor did authors observe significant positive associations with most anatomical cancer sites evaluated including oral cavity, colon, alllymphohematopoietic cancers combined and non-Hodgkin lymphoma (NHL) (Rusiecki et al., 2006). Authors reported that results did not differ by use of either the lifetime exposure day or the intensity-weighted (i

. e. , use of PPE) exposure metric , or by use of different referent groups (the no exposed or low exposed referent, data not shown). Researchers observed an unexpected inverse association with prostate cancer - 40% decreased risk ofprostate cancer among metolachlor users, but this finding was not observed in early evaluations ofprostate cancer (Alavanja et al. 2003) and the measure of statistical trend across categories, although monotonically decreasing, was not statistically significant (P>0.05).

1 CA 10861 reported hypertension, no case narrative pro vided Page 4 of7Rusiecki and colleagues reported an increased risk of lung cancer in association with metolachlor use; this finding was also reported previously in the cohort (Alavanja et al. , 2004). Comparing the highest versus lowest metolachlor exposure category, Rusiecki and colleagues observed a borderline statistically significantly increased risk of lung cancer 2.37 (95% CI 0.97, 5.82, p for trend <0.05); however the measure was imprecise due to a small number of metolachlor exposed cancer cases (-10 per category). Authors note that given the timing ofpesticide exposure information collection , these results reflect use of metolachlor only, and not S-metolachlor (in 1999 all formu la tions changed to S-metolachlor). In the previous AHS lung cancer, Alavanja et al. (2004) also reported increased risk (odds ratio) of lung cancer in relation to metolachlor use: Q 1: 1.0 , Q2: 1.6, Q3: 1.2, and Q4:5.0, p for trend 0.002. In this study, authors adjusted for various metrics of smoking (former, current, never; pack years) because smoking is a major risk for lung cancer, and the results did not change. However authors acknowledge the potential for additional residual confounding due to smoking due to the difficulty of measuring this effect accurately in lung cancer studies. Both of these AHS lung cancer-metolachlor evaluation s were published prior to the update of the AHS exposure algorithm which more evenly weights dermal and inhalation exposures; therefore, future evaluations will be less biased in this regard, and may present a more accurate estimation ofpotential risk among those exposed. There is a molecular epidemiology study within the cohort that provides additional information as to the potential carcinogenicity of metolachlor, as well as other pesticides. Telomeres are genetic material at the end of chromosomes that reduce in length after each cell division eventually triggering cell death. The mechani sms of telomere shortening are similar to suspected mechanisms of carcinogenicity and include oxidative stress and inflammation, generally. Telomere length has been associated with cancer risk in some studies. In the AHS, authors measured relative telomere length (RTV) among 1,234 healthy (non-cancer) male participants in the cohort in relation to reported pesticide use (Hou et al., 2013). Authors hypothesized that pestic ide exposure may affect telomere shortening. The authors reported significant reduction in relative telomere length (RTL) in association with lifetime use of metolachlor (RTL 1.24±0.41 to 1.16± 0.33, p=0.002) (Hou et al., 20 13). It is possible metolachlor and other pesticides may influence cancer etio logy through telomere length reduction

- however this hypothesis has not been tested yet within the Study. In another cancer epidemiology study investigating a novel hypothesis regarding the mediating role of obesity (measured as body mass index (BMI)), Andreotti et al. (20 1 0) reported a modest increased risk of colorectal cancer in relation to metolachlor use among those with an elevated body mass index (BMI): RR 1.09 (95% CI 1.04, 1.15) , p=0 .02) indicating a possible combined effect of the herbicide exposure through BMI with colorectal cancer. These results have not been rep licated and the biological mechanisms are unclear. Among other anatomical cancer sites investigated in relation to (all) pesticide use, metolachlor use was not associated with either pancreatic, colorectal, prostate or breast cancers, or was the herbicide u se associated with cutaneous melanoma (Alavanja et al., 2003; Andreotti et al., 2009; Dennis, Lynch, Sandler, & Alavanja, 2010; Engel et al., 2005 ; Koutros et al. , 2013; Lee et al., 2007)

. Metolachlor was among several pesticides included in an exposure assessment study within the AHS designed to determine level of track-in or non-intentional pesti cide exposure. Results indicate the chemical, likely due to its common use in agriculture, is detected in the home environment as a result of agricultural use (B. Curwin, Sanderson, Reynolds , Hein, & Alavanja, Page 5 of72002; B. D. Curwin> Hein> Sanderson> Barr> et al., 2005; B. D. Curwin> Hein> Sanderson, Nishioka> et al., 2005). Concerning non-cancer health outcomes, Slager and colleagues report a slight increased risk ofrhinitis in association with the herbicides use> controlling for other farm related exposures relating of wheat and corn production (Slager et al., 2009; Slager et al., 20 I0). The Agricultural Health Study has published two papers 2004 and 2006) which associate metolachlor with a possible role in lung cancer etiology. Strengths of these findings include the study des ign and sample size> valid and reliable exposure assessment> and control for potentially confounding variables including use of other pestic ides and smoking. However> authors note that several pesticides in addition to this herbicide were linked with lung cancer in the cohort> multiple comparison were not adjusted due to lack of method to adjust in non-independent exposures data> and residual or uncontrolled confounding due to smoking could have played a role. Future studies will utilize the updated AHS exposure algorithm which more accurately reflects the influence of inhalation exposures. EPA will continue to examine this literature> particularly follow-up studies in the cohort on lung cancer utilized update exposure data and exposure algorithm. 

### IV. CONCLUSION There does not appear to be a concern at this time that would warrant further investigation, since there is a low frequency ofreported incidents involving metolachlor reported to IDS and SENSOR-Pesticides. Research studies within the AHS cohort observed an association between metolachlor and lung cancer in two separate evaluations, one in 2004 (Alanvanja) and an updated one in 2006 (Rusiecki). The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

Page 6 of7Citations: Alavanja, M. C., Dosemeci, M., Samanic, C., Lubin , J., Lynch, C. F., Knott, C.,

... Blair, A. (2004). Pesticide s and lung cancer risk in the agricultural hea lth study cohort. Am J Epidemiol, 160(9), 876-885. doi: 10 .1093/aje/kwh290 Alavanja, M. C., Samanic, C., Dosemeci, M., Lubin, J., Tarone, R., Lynch, C. F.,

... Blair, A. (2003). Use of agricultural pesticides and prostate cancer risk in the Agricultural Health Study cohort. Am J Epidemiol, 157(9), 800-814. Andreotti, G., Freeman, L. E., Hou, l., Coble, J., Rusiecki, J., Hoppin, J. A.,

... Alavanja, M. C. (2009). Agricultural pesticide use and pancreatic cance r risk in the Agricultural Health Study Cohort

. lnt J Cancer, 124(10), 2495-2500. doi: 10 .1002/ijc.24185 Andreotti, G., Hou, L., Beane Freeman, L. E

. , Mahajan, R., Koutros, S., Coble, J.,

... Alavanja , M. (2010). Body mass index, agricultura l pesticide use, and cancer incidence in the Agri cultural Health Study cohort. Cancer Causes Control, 21(11), 1759 -1 775. doi: 10.1007/s10552-010-9603-9 Curwin, B., Sanderson, W ., Reynolds, S., Hein, M

., & Alavanja, M. (2002)

. Pesticide use and practices in an Iowa farm family pesticide exposure study. JAgric Saf Health, 8(4), 423-433. Curwin, B. D., Hein , M. J., Sanderson, W

. T., Barr, D. B., Heederik, D., Reynolds, S. J. , ... Alavanja, M. C. (2005). Urinary and hand wipe pesticide levels among farmers and nonfarmers in Iowa. 1 Expo Anal Environ Epidemiol, 15(6), 500-508. doi: 10.1038/sj

.jea.7500428 Curwin, B. D., Hein, M. J., Sanderson, W. T. , Nishioka, M.G., Reynolds, S. J., Ward, E. M., & Alavanja, M. C. (2005). Pesticide contamination inside farm and nonfarm homes. J Occup Environ Hyg, 2(7 ), 357
- 367. doi: 10.1080/15459620591001606 Dennis, L. K

., Lynch, C. F

. , Sandler, D. P., & Al a vanja, M. C. (2010)

. Pesticide use and cutaneous melanoma in pesticide applicators i n the agricultural heath study. Environ Health Perspect, 118(6) , 812
-817. doi: 10

. 1289/ehp.0901518 Engel, L. S., Hill, D. A., Hoppin, J. A., Lubin, J. H., Lynch, C. F., Pierce, J.,

... Alavanja, M. C. (2005)

. Pesticide use and breast cancer risk among farmers' wives in the agricultural health study. Am 1 Epidemiol, 161{2), 121-135. doi: 161/2/121 [pii] 10.1093/aje/kwi022 Hou, L., Andreotti, G., Baccarelli, A

. A., Savage, S., Hoppin, J. A., Sandler, D.P.,

... Alavanja, M. C. (2013). Lifetime Pesticide Use and Te l omere Shortening among Male Pesticide Applicators in the Agricultural Health Study. Environ Health Perspect. doi: 10.1289/ehp .1 206432 Koutros, S., Beane Freeman, L. E., Lubin, J. H., Heltshe , S. L. , Andreotti, G., Barry, K. H.,

... Alavanja, M. C. {2013). Risk of total and aggressive prostate cancer and pesticide use in the Agricultural Health Study. Am J Epidemiol, 177(1), 59- 74. doi : 10.1093/aje/kws225 Lee, W. J., Sandler, D

. P., Blair, A., Samanic, C., Cross, A. J., & Alavanja, M. C. R. (2007)

. Pesticide use and co lo recta l cancer risk in the Agricultural Health Study. Internat ional Journal of Cancer, 121(2), 339
- 346. doi: 10 .1002/ijc.22635 Rusiecki, J. A., Hou, L., Lee, W. J., Blair, A., Dosemec i , M., Lubin , J

. H.,

... Alavanja, M. C. (2006). Cancer incidence among pesticide applicators exposed to metolachlor in the Agricultural Health Study

. lnt 1 Cancer, 118(12), 3118-3123. doi: 10.1002/ijc.21758 Slager, R. E., Poole , J. A., LeVan, T. D., Sand l er, D.P., Alavanja, M. C. R

. , & Hoppin, J. A.**(2009~.** Rhinitis associated with pesticide exposure among commercial pesticide applicators in the Agricultural Health Study. Occupational and Environmental Medicine, 66(11), 718-724. doi: 10.1136/oem.2008.041798 Slager, R. E., Simpson, S. L., Levan , T. D., Poole, J

. A., Sandier, D.P., & Hoppin, J. A. (2010). Rhinitis associated with pesticide use among private pesticide applicators in the agricultural health study. J Toxicol Environ Health A, 73(20), 1382-1393. doi: 10.1080/15287394.2010.497443 

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